Telomeres are essential for chromosome stability. They ensure effective protection of chromosome ends, and are replicated by a dedicated enzyme, the telomerase reverse transcriptase. Telomeres consist of repeats of the TTAGGG sequence and end with a150-300 nucleotides-long TTAGGG single stranded overhang. The six protein complex shelterin specifically binds to telomeres, regulates their length and replication, and ensures their protection. The unprotected telomere can elicit a DNA damage response leading to cellular senescence or apoptosis. The shelterin complex is able to repress such a response by preventing the activation of ATM and ATR at telomeres. The central hypothesis of this proposal is that the LIM domain proteins TRIP6 and LPP, which have been implicated by our group in the repression of the DNA damage response at telomeres, specifically interact with shelterin and participate in the repression of ATM or ATR. The proposed experiments seek to understand the molecular interactions between TRIP6, LPP and shelterin, how and when they are recruited to telomeres, and the mechanisms and pathways involved in repressing the DNA damage response at telomeres. This work will uncover important aspects of the suppression of senescence or apoptosis in human cells, which are both potent tumor suppressor mechanisms. The proposed research will establish the role of unexplored activities at telomeres and point to possible new targets to inhibit the onset or maintenance of the transformed state at the cellular level. PUBLIC HEALTH RELEVANCE: Most human cells have a finite replication potential, and after a number of divisions reach an irreversible cell cycle arrest termed senescence, a potent tumor suppressor mechanism. Tumor cells have acquired infinite replication potential owing to the acquisition of the capacity to escape senescence, often by re-expression of telomerase. Senescence is associated with a progressive increase in the activation of DNA damage responses at telomere. This proposal focuses on novel activities which contribute to suppress the DNA damage response at telomeres, and that are expected to be important factors playing a role in cellular transformation.